Use of a combination of amoxycillin and clavulanate in the manufacture of a medicament for the treatment drug-resistant streptococcus pneumo-nia

ABSTRACT

Infections potentially caused by DRSP may be treated by a method which comprises administering a pharmaceutical formulation comprising either: for an adult or older child patient from 800 to 1100 mg amoxycillin and from 100 to 150 mg clavulanate in a weight ratio between 6:1 and 10:1 inclusive; or for a paediatric patient from 30 to 40 mg/kg body weight of amoxycillin and from 3 to 8 mg/kg body weight of clavulanate in a weight ratio between 6:1 and 10:1 inclusive; in combination with a pharmaceutically acceptable carrier or excipient, three times a day(tid).

[0001] This invention relates to an empiric method of treatment forbacterial infections potentially caused by drug resistant Streptococcuspneumoniae using formulations comprising amoxycillin and a salt ofclavulanic acid (hereinafter termed “clavulanate” unless a specific saltis identified).

[0002] The combination of amoxycillin and clavulanate is an effectiveempirical treatment for bacterial infections and may be administered byoral dosing, for instance in the form of tablets, and, for paediatricformulations, aqueous solutions or suspensions, typically as a flavouredsyrup.

[0003] Clavulanate is a β-lactamase inhibitor and is included with theβ-lactam antibiotic amoxycillin to counter a β-lactamase mediatedresistance mechanism. Some microorganisms such as Streptococcuspneumoniae have resistance mechanisms which are not β-lactamasemediated. WO94/16696 discloses generally that potassium clavulanate mayenhance the effectiveness of beta-lactam antibiotics such as amoxycillinagainst microorganisms having a resistance mechanism which is notβ-lactamase mediated.

[0004]Streptococcus pneumoniae is an important pathogen in respiratorytract infection in the community. Spneumoniae is the most commonlyimplicated bacterium in the important respiratory tract infections ofotitis media in paediatrics and sinusitis in patients of all ages andacute exacerbations of bronchitis and pneumococcal pneumonia in adults.There have been increasing reports in Europe and the U.S. of theemergence of DRSP (drug-resistant Streptococcus pneumoniae) withdecreased suspectibility to β-lactam and other antibiotics.

[0005] Whilst confirmed cases of DRSP infection may be successfullytreated with relatively high levels of amoxycillin, there still remainsthe need to develop effective empiric treatments, where DRSP may besuspected, for instance in an area with a high prevalence of DRSP, butwhere other, β-lactamase producing, organisms may also be present.

[0006] International Application WO 97/09042 (SmithKline Beecham Corp)(published after the priority date of the present application) describesformulations for treating DRSP comprising potassium clavulanate andamoxycillin characterised by a relatively high amount of amoxycillin anda twice daily (bid) dosage regimen. Preferred formulations comprise aratio of 14:1 (amoxycillin:clavulanate), with a typical dosage regimenfor paediatrics being 90/6.4 mg/kg/day and for adults 3500/250 mg/day,taken as as two equal dosages, 12 hours apart (bid).

[0007] International Application WO 96/34605 (SmithKline Beechamplc/Corp) (published after the priority date of the present application)descibes paediatric formulations comprising a 7:1 ratio of amoxycillinand clavulanate, for use in a twice daily dosing regimen (bid), suchthat the total daily dosage is 70/10 mg/kg/day.

[0008] International Application WO 95/28927 (SmithKline Beeechain Corp)describes tablets comprising 875mg amoxycillin and 125 mg clavulanate,for use in a bid regimen, such that the total daily dosage is 1750/250mg/day.

[0009] SmithKline Beecharn markets in France a paediatric formulation(‘Nourrisson’) comprising amoxycillin and clavulanate in an 8:1 ratiofor use in a thrice daily dosing regimen (tid), such that the totaldaily dosage is 80/10 mg/kg/day.

[0010] It has now been found that empiric treatment of infectionspotentially caused by DRSP may also be successfully treated withformulations of amoxycillin/clavulanate taken three times a day (tid),rather than two times a day, using a lesser ratio of amoxycillin toclavulanate.

[0011] Accordingly, the present invention provides a method of treatmentof infections potentially caused by DRSP which method comprisesadministering to a patient in need thereof a pharmaceutical formulationadapted for oral administration comprising either:

[0012] for an adult or older child patient, from 2500 to 3250 mg/kgamoxycillin per day and from 350 to 400 mg/kg clavulanate per day in aweight ratio between 6:1 and 10:1 inclusive; or

[0013] for a paediatric patient, from 75 to 125 mg/kg amoxycillin perday and from 12 to 18 mg/kg clavulanate per day in a weight ratiobetween 6:1 and 10:1 inclusive; in combination with a pharmaceuticallyacceptable carrier or excipient

[0014] Suitably, the method is used for the empiric treatment ofinfections, potentially caused by DRSP, in particular respiratory tractinfections such as otitis media in paediatrics, sinusitis and pneumoniain patients of all ages and acute exacerbations of bronchitis in adults

[0015] The invention also provides for the use of amoxycillin andclavulanate in the manufacture of a medicament for the empiric treatmentof infections potentailly potentially caused by DRSP which medicamentcomprises:

[0016] for an adult or older child patient, from 800 to 1100 mgamoxycillin and from 100 to 150 mg clavulanate in a weight ratio between6:1 and 10:1 inclusive; or

[0017] for a paediatric patient, from 30 to 40 mg/kg body weight ofamoxycillin and from 3 to 8 mg/kg body weight of clavulanate in a weightratio between 6:1 and 10:1 inclusive; the medicament being taken threetimes a day (tid).

[0018] Suitably, the dosage is administered tid, for example in three,preferably equal, unit doses per day, suitably around eight hours apart.

[0019] The weight ratios of amoxycillin:clavulanate expressed herein areas free acid equivalent. Preferred arnoxycillin:clavulanate ratios arebetween 6.5:1 to 7.5:1 inclusive, especially about 7:1 or between 7.5:1and 8.5: 1, especially about 8:1.

[0020] In the formulations of the invention the amoxycillin ispreferably in the form of amoxycillin trihydrate, although sodiumamoxycillin, for example the crystalline form of sodium amoxycillinwhich is disclosed in EP 0131147 A may also be used.

[0021] Clavulanate is preferably in the form of potassium clavulanate.Potassium clavulanate is extremely moisture-sensitive and should bestored and handled in conditions of 30% RH or less, ideally as low aspossible. Solid dosage forms should be packaged in atmosphericmoisture-proof containers, and such forms and/or their containers maycontain a desiccant.

[0022] Suitably, the dosage is administered in three, preferably equal,unit doses per day, suitably around 8 hours apart

[0023] The formulations of the invention may be made up into soliddosage forms for oral administration by a method conventional to the artof pharmaceutical technology, e.g. tablets or powder or granularproducts for reconstitution into a suspension or solution. Suitableingredients and suitable methods for making such tablets are disclosedin for example GB 2 005 538-A, WO 92/19227 and WO 95/28927. Powder orgranular formulations, such as paediatric suspension formulations, maybe manufactured using techniques which are generally conventional in thefield of manufacture of pharmaceutical formulations and in themanufacture of dry formulations for reconstitution into suchsuspensions. For example a suitable technique is that of mixing drypowdered or granulated ingredients for loading into a suitablecontainer.

[0024] For paediatric dosing, the formulations of the invention arepreferably made up into a sweet flavoured aqueous syrup formulation ofgenerally conventional formulation (except for its novel amoxycillin:clavulanate ratio and intended use) containing a suitable weight of thearnoxycillin and clavulanate in a unit dose volume, e.g. 5 ml or 2.5 mlof the syrup. Because of the water-sensitivity of clavulanate it ispreferred to provide such a syrup formulation as dry powder or granulescontained in an atmospheric moisture-proof container or sachet for makeup with water or other suitable aqueous medium shortly prior to use.

[0025] The formulation of this invention will normally, in addition toits active materials amoxycillin trihydrate and potassium clavulanate,also include excipients which are standard in the field of formulationsfor oral dosing and used in generally standard proportions, and atgenerally standard particle sizes and grades etc.

[0026] In the case of paediatric oral suspensions, these excipients maycomprise suspending aids, glidants (to aid filling), diluents, bulkingagent, flavours, sweeteners, stabilisers, and in the case of dryformulations for make up to an aqueous suspension, an edible desiccantto assist preservation of the potassium clavulanate against hydrolysisby atmospheric moisture on storage. Potassium clavulanate is normallysupplied in admixture with silicon dioxide as diluent.

[0027] Suitable excipients for use include xantham gum (suspension aid),colloidal silica (glidant), succinic acid (stabiliser), aspartame(sweetener), hydroxypropyl-methylcellulose (suspension aid) and silicondioxide (desiccant, diluent for potassium clavulanate and bulkingagent). Flavours may comprise common flavours such as orange, banana,raspberry and golden syrup, or mixtures thereof, to suit localrequirements.

[0028] Generally the proportion of active materials amoxycillintrihydrate and potassium clavulanate in a dry formulation for make upwith aqueous media into a solution, suspension or syrup formulation ofthe invention may be around 30-80 wt %.

[0029] The formulations of the invention may be adapted to paediatricdosing, i.e. to patients aged between 3 months to 12 years. Suchformulations may be dosed in daily quantities up to the maximum normalpermitted dose of amoxycillin and clavulanate.

[0030] A suitable dosage for paediatric patients is from 75 to 125mg/kgamoxycillin per day and from 12 to 18 mg/kg clavulanate per day.Preferably, the dosage is 35±10%, especially ±5%, mg/kg amoxycillin and5±10%, especially ±5%, mg/kg clavulanate (i.e. nominally a 7:1 ratio)administered tid.

[0031] A suitable dosage for older children and adult patients is from2500 to 3250 mg/kg amoxycillin per day and from 350 to 400 mg/kgclavulanate per day. Preferably, the dosage is 875±10%, especially ±5%,mg amoxycillin and 125±10%, especially ±5%, mg clavulanate (i.e.nominally a 7:1 ratio), or 1000±10%, especially ±5%, mg amoxycillin and125±10%, especially ±5%, mg clavulanate (i.e. nominally a 8:1 ratio),administered tid.

[0032] The formulation of the invention may for example be provided insolid unit dose forms embodying suitable quantities for theadministration of such a daily dose. For example a unit dosage form maybe tablets, or sachets containing granules or powders forreconstitution, one or two of which are to be taken at each tid dosinginterval. Alternatively a unit dose may be provided as a bulk of solidor solution or suspension, e.g. as a syrup for paediatricadministration, together with a suitable measuring device of known typeto facilitate administration of a suitable unit dose quantity of theformulation. A suitable unit dose quantity is one which enables theadministration of the above-mentioned daily dosage quantity dividedbetween three tid doses.

[0033] For paediatric patients, a suitable unit dose quantity ispreferably one which enables the administration of the above-mentioneddaily dosage quantity in a volume of a solution or suspension suitablefor oral administration to a paediatric patient, preferably of between2.5 to 10 ml, preferably as a syrup. A paediatric formulation maytherefore comprise a bulk of a solution or suspension, e.g. a syrup, orgranules or powder which can be made up into such a solution orsuspension, at a concentration of solution or suspension which containssuch a dose in such a volume. Suitable such formulations are describedin International application no PCT EP96/01881 (SmithKline Beecham).

[0034] For adults, a suitable unit dose may be provided in a tablet. Asuitable tablet comprising 875 mg amoxycillin and 125 mg clavulanate ismarketed by SmithKline Beecham in several countries and is alsodescribed in WO 95/28927 (SmithKline Beeecham).

EXAMPLE 1 Paediatric Formulation

[0035] The formulations listed below were prepared as dry powdermixtures, using conventional techniques. The proportions of ingredientsare expressed as mg/5 ml dose of reconstituted aqueous suspension, theformulations nominally comprising either 200 or 400 mg of amoxycillinper 5 ml of dose: Ingredient mg/5 ml mg/5 ml amoxycillin trihydrate*408.0 204.0 potassium clavulanate* 61.56 30.78 xanthan gum 12.5 12.5colloidal silica 25.0 25.0 succinnic acid 0.84 0.84 flavour 50.00 50.00aspartame 12.50 12.50 hydroxypropylmethylcellulose 79.65 79.65 silicondioxide to 885.5 to 537.5

EXAMPLE 2 Tablet Formulation

[0036] A tablet formulation comprising 875 mg amoxycillin and 125 mgclavulanate was prepared having the following composition: Ingredient mgwt. % Active Constituents: Amoxycillin trihydrate 1017.4 70.2(equivalent to amoxycillin) 875.00 Potassium clavulanate 152.45 10.5(equivalent to clavulanic 125.0 acid) Other Constituents: MagnesiumStearate 14.50 1.00 Sodium Starch Glycollate 29.00 2.00 ColloidalSilicon Dioxide 10.0 0.70 Microcrystalline Cellulose 226.65 15.6 Coretablet weight 1450.00 100.00

[0037] The tablets are made by blending the amoxycillin, potassiumclavulanate, and portions of microcrystalline cellulose and magnesiumstearate, roller compacting this blend, then blending with the otherconstituents, before tabletting on a conventional tablet press andcoating. The tablet core is coated with a film (Opadry WhiteYS-1-7700/Opadry White OY-S-7300 ex Colorcon) from an aqueous solventsystem, to give tablets with a nominal coated weight of 1482 mg. Furtherdetails of how the tablets are manufactured are provided in WO 95/28927(SmithKline Beecham).

[0038] Similar tablets can be made in which the roller compaction stepis replaced by slugging and /or a final film coating is applied from anorganic solvent system such as dichloromethane rather than an aqueoussolvent system.

1. The use of amoxycillin and clavulanate in the manufacture of amedicament for the empiric treatment of infections potentaillypotentially caused by DRSP which medicament comprises: for an adult orolder child patient, from 800 to 1100 mg amoxycillin and from 100 to 150mg clavulanate in a weight ratio between 6:1 and 10:1 inclusive; or fora paediatric patient, from 30 to 40 mg/kg body weight of amoxycillin andfrom 3 to 8 mg/kg body weight of clavulanate in a weight ratio between6:1 and 10:1 inclusive; the medicament being taken three times a day(tid).
 2. A use as claimed in claim 1 in which the ratio of amoxycillinto clavulanate is between 6.5:1 and 7.5:1 inclusive or 7.5:1 to 8.5:1.3. A use as claimed in claim 1 in which the ratio of amoxycillin toclavulanate is about 7:1 or about 8:1.
 4. A use as claimed in any one ofclaims 1 to 3 in which amoxycillin is in the form of amoxycillintrihydrate.
 5. A use as claimed in any one of claims 1 to 4 in whichclavulanate is in the form of potassium clavulanate.
 6. A use as claimedin claim 1 in which the dosage quantity for paediatric patients is35±10% mg/kg amoxycillin and 5±10% mg/kg clavulanate.
 7. A use asclaimed in claim 1 in which the dosage amount for an older child or anadult patient is 875±10% mg amoxycillin and 125±10% mg clavulanate or1000±10% mg amoxycillin and 125±10% mg clavulanate.
 8. A use as claimedin any one of claims 1 to 6 in which the formulation is adapted foradministration to paediatric patients in the form of a powder orgranular product for reconstitution into a suspension or solution andwhich comprises about 200 mg/unit dose volume of amoxycillin and 28.6mg/unit dose volume of clavulanate or 400 mg/unit dose volume ofamoxycillin and 57.2 mg/unit dose volume of clavulanate whenreconstituted.
 9. A use as claimed in any one of claims 1 to 5 or claim7 in which the formulation is in the form of tablets and adapted toprovide about 875 mg amoxycillin and 125 mg clavulanate per unit dose.10. A method of treatment of infections potentially caused by DRSP whichmethod comprises administering to a patient in need thereof apharmaceutical formulation adapted for oral administration comprisingeither: for an adult or older child patient from 800 to 1100 mgamoxycillin and from 100 to 150 mg clavulanate in a weight ratio between6:1 and 10:1 inclusive; or for a paediatric patient from 30 to 40 mg/kgbody weight of amoxycillin and from 3 to 8 mg/kg body weight ofclavulanate in a weight ratio between 6:1 and 10:1 inclusive; incombination with a pharmaceutically acceptable carrier or excipient,three times a day (tid).